Summary of Work: These studies identify critical target genes and alterations in genes that may be important in chemical carcinogenesis. Genetic alterations in oncogenes (eg.-ras) and tumor suppressor genes (eg. - p53 and p16) from rodent tumors induced by certain carcinogens and from human cancers of individuals exposed to environmental agents are being characterized in order to understand mechanisms of chemical carcinogenesis. In one set of investigations H-ras and K-ras mutation frequencies and profiles are being compared in lung and harderian tumors from B6C3F1 mice exposed to isoprene, chloroprene and butadiene in order to study mechanisms of carcinogenesis of these structurally related compounds. In another study comparative genomic hybridization (CGH) is being used to screen mouse lung tumors induced by methylene chloride for genetic losses or gains. The mechanism of methylene chloride carcinogenesis is still unclear, and our findings may indicate regions of oncogene or tumor suppressor gene involvment. A set of human bladder tumors from a cohort of people occupationally exposed to benzidine is also being examined by CGH for gains or losses of genetic material. We are also continuing our study to identify murine lung tumor susceptibility genes that may have relevant human homologs. In collaboration with Drs. Ming You and Michael Festing we identified a locus (designated Par2) on distal chromosome 18 that may represent an important tumor resistance gene in BALB/c mice. This gene maps to the region of synteny with human chr. 18q21.1 that harbors the DCC, DPC4 and JV18-1 genes that are putative tumor suppressor genes. We have now completed a study that examined the mouse homologs of DPC4 and JV18-1 (Smad4 and Smad2) as candidate genes for the Par2 mouse lung tumor resistance gene. We found no evidence to indicate that either Smad4 or Smad2 is involved in mouse lung tumorigenesis or is a good candidate for the Par2 lung tumor resistance locus on distal chr. 18.